Bidirectional Mendelian randomization and potential mechanistic insights into the causal relationship between gut...

Malignant mesothelioma (MM) is a rare but aggressive cancer originating from mesothelial cells, which presents significant challenges to patients' physical and psychological well-being. The gut-lung axis underscores the connection between gut microbiota and respiratory diseases, with emerging evidence suggesting a strong association between gut microbiota and the development of MM. In this study, we conducted a two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between gut microbiota and MM, while also exploring the underlying mechanisms through bioinformatics approaches. Gut microbiota summary data were obtained from the MiBioGen consortium, while MM data were sourced from the FinnGen R11 dataset. Causality was examined using the inverse variance weighted method as the primary analysis. Additional methods, including the weighted median, simple mode, MR-Egger, and weighted mode, were also employed. The robustness of the findings was validated through sensitivity analyses, and reverse causality was considered to further strengthen the MR results. Moreover, bioinformatics analyses were conducted on genetic loci associated with both gut microbiota and MM to explore potential underlying mechanisms. Our study suggests that genetically predicted increases in class.Bacilli, family.Rikenellaceae, genus.Clostridium innocuum group, and order.Lactobacillales were suggestively associated with a higher risk of MM, whereas increases in genus.Ruminococcaceae UCG004, genus.Flavonifractor, phylum.Firmicutes, genus.Anaerofilum, genus.Clostridium sensu stricto 1, and genus.Lactobacillus appeared to confer protective effects. Bioinformatics analysis indicated that differentially expressed genes near loci associated with gut microbiota might affect MM by modulating pathways and the tumor microenvironment. The results of this study point to a potential genetic predisposition linking gut microbiota to MM. Further experimental validation is crucial to confirm these candidate microbes, establish causality, and elucidate the underlying mechanisms.